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© 1995 Oxford University Press

research-article

Species variation in the metabolism of 15,16-dihydro-11- methylcyclopenta[a]phenanthren-17-one to its 3,4-dihydrodiol, the proximate carcinogen

G.W. Boyd 1, M.M. Coombs 2, C. Ioannides, D.F.V. Lewis, J. Snelling and A. Tsakalof

Molecular Toxicology Group, School of Biological Sciences, University of Surrey Guildford, Surrey GU2 5XH, UK
1Present address: Department of Medical Chemistry, Hansen Building, Purdue University Guildford, Surrey GU2 5XH, UK
2Department of Chemistry, University of Surrey 69, Fukuoka 8 12-82, Japan
3Permanent address: Medical School, University of Thessaly 41222 Larissa, Greece

The title compound is a strong carcinogen, similar in potency to benzo[a]pyrene in mouse skin assay. This paper describes a comparison of its in vitro metabolism by hepatic microsomal preparations from mouse, rat, rabbit, hamster, dog, monkey and man. Metabolites were isolated by preparative high pressure liquid chromatography from the ethyl acetate extractable material and their structures tentatively assigned on the basis of their retention times and ultraviolet spectra, when possible by direct comparison with authentic synthetic specimens. Mass spectrometry was then used to confirm these assignments. All these animals produce the same range of metabolites derived exclusively from oxidation at the benzoring A, the five-membered ring D, and at the 11-methyl group. However, the amounts of individual metabolites varied substantially. In particular all the animals yielded the proximate carcinogen 3,4-dihydroxy-11-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one, from which it is reasoned that all might be susceptible to its carcinogenic action. A rationalization for the observed distribution of the metabolites is proposed on the basis of a molecular model of the active site of cytochrome P450 1A1, the oxidative enzyme involved.


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